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Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)

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ClinicalTrials.gov Identifier: NCT03291288
Recruitment Status : Active, not recruiting
First Posted : September 25, 2017
Results First Posted : March 19, 2020
Last Update Posted : September 24, 2020
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo, Inc.

Tracking Information
First Submitted Date  ICMJE September 19, 2017
First Posted Date  ICMJE September 25, 2017
Results First Submitted Date  ICMJE February 12, 2020
Results First Posted Date  ICMJE March 19, 2020
Last Update Posted Date September 24, 2020
Actual Study Start Date  ICMJE February 26, 2018
Actual Primary Completion Date September 26, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2020)
  • Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Tolbutamide [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Tolbutamide [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Tolbutamide [ Time Frame: Baseline to 15 days post treatment ]
    Plasma samples for tolbutamide were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15).
  • Overall Summary of Treatment-emergent Adverse Events [ Time Frame: Baseline to 1 year post treatment ]
    Adverse events that emerge during treatment, having been absent pre-treatment, or worsens relative to the pre-treatment state.
Original Primary Outcome Measures  ICMJE
 (submitted: September 20, 2017)
  • Maximum concentration (Cmax) for midazolam [ Time Frame: within 17 days ]
    Plasma samples for midazolam will be collected at predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 24, and 48 h (±10 min up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 5 to 7 and Days 15 to 17
  • Cmax for S-warfarin [ Time Frame: within 19 days ]
    Plasma samples for S-warfarin will be collected at predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 (±1), 24 (±2), 48 (±2), 72 (±2), and 96 (±2) h on Days 1 to 5 and also when co-administered with pexidartinib on Days 5 (to 9) and 15 (to 19).
  • Time to maximum concentration (Tmax) for midazolam [ Time Frame: within 17 days ]
  • Tmax for S-warfarin [ Time Frame: within 19 days ]
  • Area under the curve to the last observable concentration (AUClast) for midazolam [ Time Frame: within 17 days ]
  • AUClast for S-warfarin [ Time Frame: within 19 days ]
  • Number of participants with an adverse event by the end of Part 2 [ Time Frame: 1 year ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 5, 2020)
  • Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Pexidartinib and ZAAD-1006a Metabolite [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
  • Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Pexidartinib and ZAAD-1006a Metabolite [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
  • Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Pexidartinib and ZAAD-1006a Metabolite [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for pexidartinib and its metabolite were collected at predose, 0.5, 1, 2, 2.5, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 3, and at steady state when co-administered with midazolam and tolbutamide on Day 13.
  • Pharmacokinetic Analysis: Maximum Concentration (Cmax) for Midazolam Metabolite, 1-Hydroxy Midazolam [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
  • Pharmacokinetic Analysis: Time to Maximum Concentration (Tmax) for Midazolam Metabolite, 1-Hydroxy Midazolam [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
  • Pharmacokinetic Analysis: Area Under the Curve to the Last Observable Concentration (AUClast) for Midazolam Metabolite, 1-Hydroxy Midazolam [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for midazolam and 1-hydroxy midazolam were to be collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8 (±10 min up to 8 h), 10 (±2), 24 (±2), and 48 (±2) hours on Days 1 to 3 and also when co-administered with pexidartinib on Days 3 to 5 and Days 13 to 15.
  • Pharmacokinetic Analysis: Metabolite to Parent Ratio (MPR) for Midazolam [ Time Frame: Baseline to 13 days post treatment ]
    Plasma samples for midazolam were collected at predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 24, and 48 hours (h) (±10 minutes up to 1 h, ±10% thereafter) on Days 1 to 3, and also when co-administered with pexidartinib on Days 3 (to 5) and Days 13 (to 15). Plasma pharmacokinetic parameters calculated for Midazolam metabolite. 1-hydroxy midazolam and midazolam for the MPR value.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2017)
  • Overall response rate (ORR) by the end of Part 2 [ Time Frame: 1 year ]
    ORR is defined as the percentage of participants who achieve a confirmed complete response (CR) or partial response (PR) based on locally read tumor assessments according to Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 or other applicable assessment of treatment response based upon the applicable tumor.
  • Cmax for pexidartinib and its metabolites [ Time Frame: within 15 days ]
    Plasma samples for pexidartinib and its metabolite will be collected at predose, 0.5, 1, 2, 3, 4, 6, 8, and 10 (±1) h after the first dose on Day 5, and at steady state when co-administered with midazolam and S-warfarin on Day 15.
  • Tmax for pexidartinib and its metabolite [ Time Frame: within 15 days ]
  • AUClast for pexidartinib and its metabolite [ Time Frame: within 15 days ]
  • Cmax for midazolam metabolite [ Time Frame: within 17 days ]
  • Tmax for midazolam metabolite [ Time Frame: within 17 days ]
  • AUClast for midazolam metabolite [ Time Frame: within 17 days ]
  • Metabolite to parent ratio (MPR) for midazolam [ Time Frame: within 17 days ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Pexidartinib on the Way the Body Processes CYP3A4 and CYP2C9 Substrates (Pharmacokinetics)
Official Title  ICMJE An Open-label, Single Sequence, Crossover Drug-drug Interaction Study Assessing the Effect of Pexidartinib on the Pharmacokinetics of CYP3A4 and CYP2C9 Substrates in Patients
Brief Summary

This study has two parts.

Part 1 will evaluate how pexidartinib affects the way the body processes CYP3A4 and CYP2C9 substrates using midazolam and tolbutamide, respectively, as probe agents.

Part 2 will test the efficacy and safety of pexidartinib treatment in various tumor types.

In Part 2, the same participants will continue to receive pexidartinib twice daily.

Participants will be allowed to continue using pexidartinib as long as the participant derives benefit.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Intervention Model Description:
Open-label, single sequence study with 2 parts
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Drug Interaction Potential
Intervention  ICMJE
  • Drug: Tolbutamide
    Commercially available tolbutamide
    Other Name: Orinase
  • Drug: Midazolam
    Commercially available midazolam
    Other Names:
    • Dormicum
    • Hypnovel
    • Versed
    • Others
  • Drug: Pexidartinib
    Pexidartinib is formulated as opaque, white, 200-mg capsules
    Other Name: PLX-3397
Study Arms  ICMJE Experimental: Pexidartinib

Part 1 (Drug-drug Interaction Phase):

On Day 1, all participants will receive a single oral dose each of midazolam (2 mg) and tolbutamide (500 mg). On Day 3, pexidartinib (800 mg/d) in twice daily (400 mg BID) dosing will be initiated and continue throughout the remainder of Part 1 and into Part 2. On the first day of pexidartinib treatment (Day 3), a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning pexidartinib dose (400 mg). On Day 13, a single dose of midazolam (2 mg) and tolbutamide (500 mg) will be co-administered with the morning dose of pexidartinib (400 mg).

Part 2 (Efficacy and Safety Phase):

All participants will continue to receive pexidartinib 400 mg BID.

Interventions:
  • Drug: Tolbutamide
  • Drug: Midazolam
  • Drug: Pexidartinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 5, 2020)
32
Original Estimated Enrollment  ICMJE
 (submitted: September 20, 2017)
30
Estimated Study Completion Date  ICMJE December 31, 2020
Actual Primary Completion Date September 26, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Is the age of majority in country of residence
  • Has a diagnosis of:

    1. tenosynovial giant cell tumor (TGCT), which is associated with severe morbidity or functional limitations and for whom surgery is not an option (prior pexidartinib is permitted for TGCT patients unless ineffective or not tolerated and there has been a washout period of at least 4 weeks)
    2. KIT-mutant tumor, including melanoma or gastrointestinal stromal tumor (GIST), for which there is no standard systemic therapy, or
    3. other solid tumors (all comers) for which there is no standard systemic therapy and there is a rationale for use of pexidartinib at the Investigator's discretion
  • If a female of childbearing potential, had a negative serum pregnancy test within 14 days before enrollment, or within 72 hours before enrollment where required
  • Is a non-sterile male or female willing to use of one of the protocol-defined highly effective contraception methods:

    1. intra-uterine device (nonhormonal or hormonal)
    2. sexual abstinence (only if this is in line with the patient's current lifestyle)
    3. barrier methods (eg, condom, diaphragm) used in combination with hormonal methods associated with inhibition of ovulation
  • Is a surgically sterile male or female, or is postmenopausal for at least 1 year, at least 50 years of age, with a follicle-stimulating hormone level > 40 milli-International units per mL (mIU/mL)
  • Has adequate hematologic, hepatic, and renal function as defined by the protocol
  • Is able and willing to follow all study procedures
  • Has provided a signed informed consent

Exclusion Criteria:

  • Is pregnant or breastfeeding
  • Is unable to swallow oral medication
  • Is unable to follow study procedures
  • Is taking or has taken any medications or therapies outside of protocol-defined parameters
  • Has any disease or condition that, per protocol or in the opinion of the investigator, might affect:

    1. safety and well-being of the participant or offspring
    2. safety of study staff
    3. analysis of results
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands,   New Zealand,   Taiwan,   United States
Removed Location Countries Korea, Republic of
 
Administrative Information
NCT Number  ICMJE NCT03291288
Other Study ID Numbers  ICMJE PL3397-A-U126
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
Responsible Party Daiichi Sankyo, Inc.
Study Sponsor  ICMJE Daiichi Sankyo, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Global Clinical Leader Daiichi Sankyo, Inc.
PRS Account Daiichi Sankyo, Inc.
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP